The treatment of pain in Sickle Cell Disease (SCD) is challenging for both patients and providers and is associated with significant disparities in healt care delivery. While the role of ongoing inflammation during vasooclusive crisis and pain is recognized, effective therapeutic interventions are lacking. Glucocorticoids, with their anti-inflammatory properties, in small clinical trials have been shown to reduce the duration of analgesic therapy in children with pain crisis, and in SCD patients admitted with acute chest syndrome, a course of dexamethasone decreased hospitalization time. However, clinicians hesitate to prescribe steroids to treat steroid-responsive conditions in SCD patients because their use is associated with complications that include increased risk of hospital readmission, rebound pain, strokes, avascular necrosis, and acute chest syndrome. Further, some steroid-responsive conditions such as asthma have a high incidence in SCD; however, because of known side-effects, clinicians hesitate to use disease-altering therapies such as steroids in SCD patients. In turn, SCD patients who have steroid-responsive conditions may receive less than ideal treatment. VBP15 is a first-in-man dissociative steroid that has optimized sub-activities of more traditional glucocorticoids, with increased efficacy and reduced side effects. VBP15 retains NFKB inhibition (transrepression) but loses GRE-mediated transactivation activities associated with side effect profiles of clinically used steroids. Preliminary data shows that VBP15 has the potential to favorably affect the alterations in pain response and some hematologic and histopathologic alterations observed in a murine model of SCD. The goal of this STTR proposal is to carry out a preclinical efficacy study of VBP15 to treat the altered pain response and to ameliorate the abnormal hematologic, biochemical, and inflammatory profiles in SCD mice.